Cyclotrimerization approach to unnatural structural modifications of pancratistatin and other amaryllidaceae constituents — Synthesis and biological evaluation

Abstract

The phenanthridone core of pancratistatin lacking all aromatic oxygenation was prepared by cyclotrimerization of acetylene-containing scaffolds 30 and 41, reflecting the natural and the C-1 epi configuration, respectively, of the amino inositol moiety. The cobalt-catalyzed formation of the aromatic core led to bisTMS derivatives 39 and 48, as well as bisacetyl derivative 51. The effectiveness of cyclotrimerization of the natural or trans series was compared with that of the cis series. In addition, the yields of cyclotrimerization were compared for propargylic amines and propargylic amides. Eleven derivatives, including the fully hydroxylated phenantridone 39, were tested against seven cancer cell lines. Three of the compounds displayed activities only an order of magnitude less than those of 7deoxypancratistatin. Full experimental and spectral details are provided for all key compounds and future projections for the preparation of unnatural analogs of Amaryllidaceae constituents are advanced, along with some new insight into the minimum pharmacophore of pancratistatin.Résumé : Faisant appel à une cyclotrimérisation des dérivés acétyléniques 30 et 41 qui reflètent respectivement les configurations naturelle et C-1-épi, on a préparé la phénanthridone, le squelette fondamental de la pancratistatine ne comportant pas d'oxygène aromatique. La formation catalysée par le cobalt du noyau fondamental à conduit aux dérivés bisTMS 39 et 48 ainsi qu'au dérivé bisacétylé 51. On a comparé l'efficacité de la cyclotrimérisation de la série nature ou trans avec celle de la série cis. De plus, on a comparé les rendements des cyclotrimérisations avec des amines et des amides propargyliques. Onze dérivés, y compris la phénantridone totalement hydroxylé (39) ont été évalués contre sept souches de cancer. Trois de ces composés présentent des activités qui ne sont qu'un ordre de grandeur inférieures à celle de la 7-désoxypancratistatine. On rapporte l'ensemble des détails expérimentaux et spectraux relatifs à tous les intermédiaires clés. Les projections relatives à la préparation d'analogues non naturels des constituants de l'Amaryllidaceae sont avancées et l'on possède déjà de nombreuses pistes nouvelles concernant la nature du pharmacophore minimal de la pancratistatine.

Chemistry, Biology, and Medicinal Potential of Narciclasine and its Congeners

“…10 times less potent than its 7-hydroxy congener. 137 Recently, Pandey and coworkers reported the results of investigations of the effects of pancratistatin on normal and cancer cells, providing evidence supporting selective toxicity of this isocarbostyril to cancer cells. Thus, pancratistatin was found to selectively induce apoptosis using non-genomic targets in Jurkat (model for human T-cell leukemia) cell line as opposed to normal nucleated blood cells.…”

Total Syntheses of Pancratistatin. A Review

“…Removal of the oxygen substituents on ring A leads to significant reduction of potency. 7-Deoxypancratistatin is about 10-fold less potent, 27 while analogue 1 (Fig. 2) with a single alkoxy group, prepared by Hudlicky and coworkers, 28 is 100-fold less cytotoxic than pancratistatin.…”

Unnatural C-1 homologues of pancratistatin — Synthesis and promising biological activities

“…For example, both 7 and 8 were about 10 times more potent than their 7-deoxy analogues ( 5 and 6 ) against the prostate DU-145 cells, and this 10-fold difference in activity is similar to that between 1 and 3 . 2a,13b In addition, the double-digit nanomolar potency of the acetoxymethyl analogue ( 8 ) is noteworthy and it approaches that of narciclasine, which was used as a reference compound. The most encouraging activity was found, however, with the benzoxymethyl compound ( 9 ).…”

“…In our group, we have been investigating various truncated derivatives of pancratistatin, and 7-deoxypancratistatin, 12 as well as derivatives with variations of functionality at the aromatic core, 13 including an indole mimic of 7-deoxypancratistatin. 14 More recently, and inspired by Pettit's report of the C-1 benzoate ester, 4c we investigated carbon homologues of 7-deoxypancratistatin at position C-1 and found that the hydroxymethyl and acetoxymethyl derivatives ( 5 and 6 , respectively) were reasonably active.…”